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Hydrolytically stable maleimide-terminated polymers |
| 7432331 |
Hydrolytically stable maleimide-terminated polymers
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| Patent Drawings: | |
| Inventor: |
Kozlowski, et al. |
| Date Issued: |
October 7, 2008 |
| Application: |
11/091,024 |
| Filed: |
March 25, 2005 |
| Inventors: |
Kozlowski; Antoni (Huntsville, AL)
Gross, III; Remy F. (Petaluma, CA)
McManus; Samuel P. (Brevard, NC)
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| Assignee: |
Nektar Therapeutics AL, Corporation (Huntsville, AL) |
| Primary Examiner: |
Rabago; Roberto |
| Assistant Examiner: |
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| Attorney Or Agent: |
Evans; Susan T. |
| U.S. Class: |
525/343; 424/78.17; 525/326.7; 525/326.9; 525/327.2; 525/328.2; 525/328.8; 525/379; 525/403; 525/50; 525/54.1; 525/55; 525/56; 525/61; 528/421; 528/487 |
| Field Of Search: |
525/50; 525/54.1; 525/55; 525/56; 525/61; 525/326.7; 525/326.9; 525/327.2; 525/328.2; 525/328.8; 525/343; 525/379; 525/403; 528/421; 528/487; 424/78.17 |
| International Class: |
C08C 19/20; A61K 47/48; C08F 8/34; C08G 65/326; C08C 19/22; C08F 8/32; C08G 65/325 |
| U.S Patent Documents: |
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| Foreign Patent Documents: |
1110681; 19652544; 0 318 162; 357110; 878482; 1046394; 0714402; 1 283 233; 2206317; 50110491; 57192418; 57205413; 58015515; 58040374; 63277619; 63286445; 01062338; 01088129; 02149335; 07132685; 08041195; 08117586; 11349877; 2000/143729; 2000/144033; 2000/144041; 2000191700; 2000/306605; 2000/319252; 2001/172554; 2001/294777; 2001/322976; 2002/121221; 2002/265442; 2002/265541; 2003/040939; 2003/221443; 2003/241337; WO 90/12874; WO 92/16221; WO 94/21235; WO 94/21281; WO 95/11987; WO 96/32841; WO 96/40285; WO 98/02743; WO 98/11919; WO 98/18500; WO 98/22092; WO 98/30575; WO 98/31383; WO 99/03887; WO 99/13919; WO 99/48918; WO 99/48928; WO 99/55837; WO 99/64460; WO 00/05582; WO 00/10974; WO 00/16733; WO 00/26256; WO 00/45856; WO 01/07484; WO 01/07577; WO 01/12154; WO01/48052; WO 01/48052; WO 01/62827; WO 02/37850; WO 02/25644; WO 02/35636; WO 02/36161; WO 02/060978; WO 02/076428; WO 02/083067; WO 02/100343; WO 03/000278; WO 03/028640; WO 03/034995; WO 03/047549; WO 03/057134; WO 03/059363; WO 03/061577; WO 03/064462 |
| Other References: |
Acevedo, et al., "Synthesis and Characterization of Imide End-Capped Oligomers of Poly(diethyleneglycol Terephthalate)," J. of Applied PolymerSci. 38(9):1745-1759 (1989). cited by other.
Acevedo, et al., "Kinetic Study Of The Crosslinking Reaction Of Flexible Bismaleimides," Polymer 31(10):1955-1959 (1990). cited by other.
Acevedo, et al., "Semi-Interpenetrating Polymer Networks Of Maleimides End-Capped Oligoesters," Polymer 32(12):2210-2214 (1991). cited by other.
Alam, et al., "The Importance Of Being Knotted: Effects Of The C-Terminal Knot Structure On Enzymatic And Mechanical Properties Of Bovine Carbonic Anhydrase II," FEBS Letters 519(1-3):35-40 (2002). cited by other.
Allen, et al., "Use Of The Post-Insertion Method For The Formation Of Ligand-Coupled Lipsomes," Cellular & Molecular Biol. Letters 7(3):889-894 (2002). cited by other.
Andreadis, et al., "Use Of Immobilized PCR Primers To Generate Covalently Immobilized Dnas For In Vitro Transcription/Translation Reactions," Nucleic Acids Research 28(2):II-VIII (2000). cited by other.
Bestman-Smith, et al., "Sterically Stabilized Liposomes Bearing Anti-HLA-DR Antibodies For Targeting The Primary Cellular Reservoirs Of HIV-1," Biochimica et Biophysica Acta 1468(1-2):161-174 (2000). cited by other.
Bieniarz, et al., "Extended Length Heterobifunctional Coupling Agents For Protein Conjugations," Biconjugate Chem. 7:88-95 (1996). cited by other.
Blessing, et al., "Different Strategies For Formation Of PEGylated EGF-Conjugated PEI/DNA Complexes For Targeted Gene Delivery," Biconjugate Chem. 12(4):529-537 (2001). cited by other.
Chian, et al., "Synthesis Of Bismaleimide Resin Containing The Poly(Ethylene Glycol) Side Chain: Curing Behavior And Thermal Properties," J. of Applied Polymer Sci. 85(14):2935-2945 (2002). cited by other.
Chain, et al., "Mechanical Properties And Morphology Of Poly(Ethylene Glycol)-Side-Chain-Modified Bismaleimide Polymer," J. of Applied Polymer Sci. 86(3):715-724 (2002). cited by other.
Chluba, et al., "Enhancement Of Gene Delivery By An Analogue Of .alpha.-MSH In A Receptor-Independent Fashion," Biochimica et Biophysica Acta 1510(1-2):198-208 (2001). cited by other.
Christakopoulos, et al., "Enhancement Of pH-Stability Of A Low Molecular Mass Endoglucanase From Fusarium Oxysporum By Protein Pegylation," Carbohydrate Res. 314(1-2):95-99 (1998). cited by other.
Dauty, et al., "Intracelular Delivery Of Nanometric DNA Particles Via The Folate Receptor," Bioconjugate Chem. 13(4):831-839 (2002). cited by other.
Derycke, et al., "Transferrin-Mediated Targeting Of Hypericin Embedded In Sterically Stabilized PEG-Liposomes," International J. of Oncology 20(1):181-187 (2002). cited by other.
Dix, et al., "Chain Extension And Crosslinking Of Telechelic Oligomers-I. Michael Additions Of Bismines To Bismaleimides And Bis(Acetylene Ketones)," Eur. Polym. J. 31(7):647-652 (1995). cited by other.
Fleiner, et al., "Studies On Protein-Liposome Coupling Using Novel Thiol-Reactive Coupling Lipids: Influence Of Spacer Length And Polarity," Bioconjugate Chem. 12(4):470-475 (2001). cited by other.
Fles, et al., "Synthesis And Spectroscopic Evidence Of N-Arylmaleidines And N-Aryl-2,3-Dimethylmaleimides," Croatica Chemica Acta, 76(1):69-74 (2003). cited by other.
Gagne, "Targeted Delivery Of Indinavir To HIV-1 Primary Reservoirs With Immunoliposomes," Biochimica et Biophysica Acta, 1558(2):198-210, (2002). cited by other.
Gaina, et al., "Bismaleimide Resins Containing Urethanic Moieties," J of Macromolecular Sci--Pure and Appl. Chem. A34(12):2435-2449 (1997). cited by other.
Gheneim, et al., "Diels-Alder Reactions With Novel Polymeric Dienes And Dienophiles: Synthesis Of Reversibly Cross-Linked Elastomers," Macromolecules 35(19):7246-7253 (2002). cited by other.
Gusens, et al., "Targeting Of The Photocytotoxic Compound A1PcS4 To Hela Cells By Transferring Conjugate PEG-Liposomes," Intern. J. of Cancer 101(1): 78-85 (2002). cited by other.
Goodson, et al., "Site-Directed Pegylation Of Recombinant Interleukin-2 At Its Glycosylation Site," Biotech. 8:343-346 (1990). cited by other.
Hai, et al., "Synthesis Of Water-Soluble, Nonimmunogenic Polyamide Cross-Linking Agents," Bioconjugate Chem. 9(6):645-654 (1998). cited by other.
Hai, et al., "Polymerization Of Diaspirin Cross-Linked Hemoglobin (DCLHb) With Water-Soluble, Non-immunogenic Polyamide Cross-Linking Agents," Bioconjugate Chem. 10(6):1013-1020 (1999). cited by other.
Heimbuch, et al., "Composites Of Vinyl Polystyrylpyridine/Bismaleimide-Aliphatic Ether Copolymers," SAMP Quarterly 20(3):17-21 (1989). cited by other.
Hill, et al., "Diels-Alder Bioconjugation Of Diene-Modified Oligonucleotides," J. Org. Chem.. 66(16):5352-5358 (2001). cited by other.
Huwyler, et al., "Bypassing Of P-glycoprotein Using Immunoliposomes," J. of Drug Targeting 10(1):73-79 (2002). cited by other.
Ishida, et al., "Targeted Delivery And Triggered Release Of Liposomal Doxorubicin Enhances Cytotoxicity Against Human B Lymphoma Cells," Biochimica et Biophysca Acta, 1515(2):144-158, (2001). cited by other.
Juszczak, et al., "UV Resonance Raman Study Of .beta.93-Modified Hemoglobin A: Chemical Modifier-Specific Effects And Added Influences Of Attached Poly(Ethylene Glycol,)" Biochemistry 41(1):376-385 (2002). cited by other.
Kirpotin et al., "Sterically Stabilized Anti-HER2 Immunoliposomes:Design And Targeting To Human Breast Cancer Cells In Vitro," Biochemistry 36(1):66-75 (1997). cited by other.
Kirchmeier, et al., "Correlations Between The Rate Of Intracellular Release Of Endocytosed Liposomal Doxorubicin And Cytotoxicity As Determined By A New Assay," J. of Liposome Res. 11(1):15-29 (2001). cited by other.
Kley, et al., "Synthesis Of Novel Thiol-Reactive Amphiphilic Lipids Based On Cholesterol For Protein-Liposome Coupling," Monatshefte fur Chemie 129(3):319-327 (1998). cited by other.
Kogan, "The Synthesis Of Substituted Methoxy-Poly(Ethyleneglycol) Derivatives Suitable For Selective Protein Modification," Synthetic Communications 22(16):2417-2424 (1992). cited by other.
Kuehne, et al., "SynthesisAand Characterization Of Membrane-Active GALA-OKT9 Conjugates," Bioconjugate Chemistry 12(5):742-749 (2001). cited by other.
Kullberg, et al., "Development Of EGF-Conjugated Liposomes For Targeted Delivery Of Boronated DNA-Binding Agents," Bioconjugate Chem. 13(4):737-743 (2002). cited by other.
Lee, et al., "A New Gene Delivery Formulation Of Polyethylenimine/DNA Complexes Coated With PEG Conjugated Fusogenic Peptide," Journal of Controlled Release 76(1-2): 183-192 (2001). cited by other.
Lu, et al., "Preparation And Biological Evaluation Of Polymerizable Antibody Fab' Fragment Targeted Polymeric Drug Delivery System," Journal of Controlled Release 74(1-3):263-268 (2001). cited by other.
Makmura, et al., "Development Of A Sensitive Assay To Detect Reversibly Oxidized Protein Cysteine Sulfydryl Groups," Antioxidants & Redox Signaling 3(6):1105-1118 (2001). cited by other.
Manjula, et al, "Cys-93-.beta..beta.-Succinimidophenyl Polyethylene Glycol 2000 Hemoglobin A. Intramolecular Cross-Bridging Of Hemoglobin Outside The Central Cavity," The J. of Biological Chemistry 275(8):5527-5534 (2000). cited by other.
Manjula, et al., "Site-Specific PEGylation Of Hemoglobin At Cys-93(.beta.): Correlation Between The Colligative Properties Of The PEGylated Protein And The Length Of The Conjugated PEG Chain," Bioconjugate Chem. 14:464-472 (2003). cited by other.
Mao, et al., "Chitosan-DNA Nanoparticles As Gene Carriers: Synthesis, Characterization And Transfection Efficiency," J. of Controlled Release 70(3):399-421 (2001). cited by other.
Maruyama, et al., "Targeting Efficiency Of PEG-Immunoliposome-Conjugated Antibodies At PEG Terminals," Advaced Drug Delivery Reviews 24(2,3):235-242 (1997). cited by other.
Maruyama, et al., "Targetability Of PEG-Immunoliposomes Conjugating Antibodies At The Ends Of PEG Chains," Polymer Preprints 38(1):541-542 (1997). cited by other.
Menezes, et al., "Cellular Trafficking And Cytotoxicity Of Anti-CD19-Targeted Liposomal Doxorubicin In B Lymphoma Cells," Journal of Liposome Research 9(2):199-228 (1999). cited by other.
Meyer, et al., "Cationic Liposomes Coated With Polyethylene Glycol As Carriers For Oligonucleotides", The J. of Biological Chemistry, 273(25):15621-15627 (1998). cited by other.
Moreira, et al., "Targeting Stealth Liposomes In A Murine Model Of Human Small Cell Lung Cancer," Biochemica et Biophysica Acta 1515(2):167-176 (2001). cited by other.
Oliver, et al., "Synthesis Of Pegylated Immunonanoparticles," Pharmceutical Res. 19(8):1137-1143 (2002). cited by other.
Perret, et al., "Versatile Decoration Of Glass Surfaces To Probe Individual Protein-Protein Interactions And Cellular Adhesion," Langmuir 18(3):846-854 (2002). cited by other.
Pierce Product Catalog "SMCC (Succinimidyl 4-[N-Maleimidomethyl]Cyclohexane-1-Carboxylate)," Product No. 22360 (2002). cited by other.
Reddy, et al., "Folate-Targeyted, Cationic Liposome-Mediated Gene Transfer Into Disseminated Peritoneal Tumors," Gene Therapy 9(22):1542-1550 (2002). cited by other.
Romani, et al., "Synthesis Of Unsymmetrical Cystine Peptides: Directed Disulfide Pairing With The Sulfenohydrazide Method," Chem. of Peptides and Proteins 2:29-34 (1984). cited by other.
Sapra, et al., "Targeting Of Immunoliposomal Vincristine To Hematological Malignancies," Proceed. Int'l. Symp. Control. Rel. Bioact. Mater. Controlled Releas Soc. 28:582-583 (2001). cited by other.
Sapra, et al., "Internalizing Antibodies Are Necessary For Improved Therapeutic Efficacy Of Antibody-Targeted Liposomal Drugs," Cancer Res. 62(24):7190-7194 (2002). cited by other.
Schmidt, et al., "Force Tolerances Of Hybrid Nanodevices," Nano Letters 2(11):1229-1233 (2002). cited by other.
Shearwater Catalog, "Polyethelene Glycol And Derivatives For Biomedical Applications," Shearwater Corporation, pp. 1-17 (2001). cited by other.
Shi, et al., "Noninvasive Gene Targeting To The Brain," Proceed. Of the Nat'l Academy of Sci. of the U.S.A. 97(13):7567-7572 (2000). cited by other.
Shi, et al., "Brain-Specific Expression Of An Exogenous Gene After I.V. Administration," Proceed. Of the Nat'l Academy of Sci. of the U.S.A. 98(22):12754-12759 (2001). cited by other.
Shukla, et al., "Synthesis And Biological Evaluation Of Folate Receptor-Targeted Boronated PAMAM Dendrimers As Potential Agents For Neutron Capture Therapy," Bioconjugate Chem. 14(1):158-167 (2003). cited by other.
Souza, et al., "Membrane-Active Properties Of .alpha.-MSH Analogs: Aggregation And Fusion Of Liposomes Triggered By Surface-Conjugated Peptides," Biochimica et Biophysica Acta 1558(2):222-237 (2002). cited by other.
Takizawa, et al., "Targetability Of The Pendant Type Polyethyleneglycol-Immunoliposomes In Vivo," Drug Delivery System 13(6):407-414 (1998). cited by other.
Tang, et al., "Preparation Of A New Pegylation Reagent For Sulfhydryl-Containg Polypeptide," Tetrahedron Letters 35(35):6515-6516 (1994). cited by other.
Tessmar, et al., "Amine-Reactive Biodegradable Diblock Copolyemrs", Biomacromolecules 3(1):194-200 (2002). cited by other.
Tsutsumi, et al., "Site-Specific Chemical Modification With Polyethylene Glycol Of Recombinant Immunotoxin Anti-Tac(Fv)-PE38 (LMB-2) Improves Antitumor Activity And Reduces Animal Toxicity And Immunogenicity," Proceed. of the Nat'l Academy of Sci.of the U.S.A. 97(15):8548-8553 (2000). cited by other.
Turner, et al., "The Transfection Of Jurkat T-Leukemic Cells By Use Of pH-Sensitive Immunoliposomes," Journal of Liposome Research 12(4):311-334 (2002). cited by other.
Vargas, et al, "Diels-Alder Modification Of Poly(Ethylene Terphthalate-Co-Anthracene-2,6-Carboxylate) With N-Substituted Maleimides," J. of Polymer Sci. 40(19):3256-3263 (2002). cited by other.
Vreeland, et al., "Molar Mass Profiling Of Synthetic Polymers By Free-Solution Capillary Electrophoresis Of DNA-Polymer Conjugates," Anal. Chem. 73(8):1795-1803, (2001). cited by other.
Wu, et al., "p53 Protein Oxidation In Cultured Cells In Response To Pyrrolidline Dithiocarbamate: A Novel Method For Relation The Amount of p53 Oxidation In Vivo To The Regulation Of p53-Responsive Genes", Biochem. J., 351(1):87-93, (2000). cited byother.
Wunsch, et al., "A New Method For The Selective Synthesis of Unsymmetrical Cystine Peptides," Peptides; Proceedings of the 17.sup.th European Peptide Symposium, pp. 183-188 (1982). cited by other.
Enzon Pharmaceuticals Catalog, "Macromolecular Engineering Technologies," pp. 1-14 (2004). cited by other.
Nektar Molecule Engineering Catalog, "Polyethylene Glycol and Derivatives for Advanced PEGylation," pp. 1-21 (2003). cited by other.
Nektar Advanced PEGylation Catalog, "Polyethylene Glycol and Derivatives for Advanced PEGylation," pp. 1-24 (2004). cited by other.
Nektar Advanced PEGylation Catalog, "Polyethylene Glycol and Derivatives for Advanced PEGylation," pp. 1-30 (2005-2006). cited by other.
NOF Corporation Catalog, "Peg Derivatives, Phospholipid and Drug Delivery Materials for Pharmaceuticals," 1: pp. 2-46 (2003). cited by other.
Polypure Products Catalog, Apr. 2005, 4 pages. cited by other.
Quanta Biodesign Catalog, "Labeling, Modification and Crosslinking Reagents Incorporating our Unique Monodispersed dPEG.TM. Technology," pp. 1-38, Mar. 12, 2004. cited by other.
Quanta Biodesign Catalog, "Labeling, Derivatization and Crosslinking Reagents for Biological and Related Materials with dPEG," pp. 1-31, Nov. 5, 2004. cited by other.
Quanta Biodesign Product Catalog, "Leading Innovator, Producer and Provider of Monodisperse Discrete PEG (dPEG) Derivatives," pp. 1-51, Nov. 17, 2005. cited by other.
Shearwater Polymers, Inc., Catalog, , "Functionalized Biocompatible Polymers for Research: Polyethylene Glycol and Derivatives," pp. 2-49 (Mar. 1995). cited by other.
Shearwater Polymers, Inc., Catalog, , "Functionalized Biocompatible Polymers for Research and Pharamceuticals: Polyethylene Glycol and Derivatives," pp. 2-53 (1997-1998). cited by other.
Shearwater Polymers, Inc., Catalog, "Functionalized Biocompatible Polymers for Research and Pharmaceuticals: Polyethylene Glycol and Derivatives," pp. 2-50 (2000). cited by other. |
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| Abstract: |
The present invention is directed to hydrolytically stabilized maleimide-functionalized water soluble polymers and to methods for making and utilizing such polymers and their precursors. |
| Claim: |
What is claimed is:
1. A conjugate comprising the following structure: ##STR00097## wherein: POLY is a water-soluble polymer segment, b is 0 or 1, X is a hydrolytically stable linker comprisingat least 3 contiguous saturated carbon atoms adjacent to the ring nitrogen atom, "POLY-[O].sub.b--C(O)--NH--X--" is absent aromatic groups and ester linkages, and "--S-biologically active agent" represents a residue of a biologically active agentcomprising a thiol (--SH) group.
2. A composition comprising the conjugate of claim 1, wherein said composition comprises a single polymer conjugate species.
3. The conjugate of claim 1, where b is 0.
4. The conjugate of claim 1, where b is 1.
5. The conjugate of claim 1, wherein X is a saturated acyclic, cyclic or alicyclic hydrocarbon chain having a total of about 3 to about 20 carbon atoms.
6. The conjugate of claim 5, wherein X is a saturated acyclic, cyclic, or alicyclic hydrocarbon chain having a total number of carbon atoms selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and20.
7. The conjugate of claim 5, wherein X is a linear saturated acyclic hydrocarbon chain.
8. The conjugate of claim 5, wherein X is a branched saturated acyclic hydrocarbon chain.
9. The conjugate of claim 8, wherein X is branched at the carbon .alpha. to the maleimidyl group.
10. The conjugate of claim 8, wherein X is branched at the carbon .beta. to the maleimidyl group.
11. The conjugate of claim 8, wherein X is branched at the carbon .gamma. to the maleimidyl group.
12. The conjugate of claim 5, having the structure: ##STR00098## wherein: y is an integer from 3 to about 20; R.sup.1, in each occurrence, is independently H or an organic radical that is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl, and R.sup.2, in each occurrence, is independently H or an organic radical that is selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl.
13. The conjugate of claim 12, wherein R.sup.1 and R.sup.2 in each occurrence is independently H or an organic radical selected from the group consisting of lower alkyl and lower cycloalkyl.
14. The conjugate of claim 13, wherein R.sup.1 and R.sup.2 are both H, and y is selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10.
15. The conjugate of claim 12 having the structure: ##STR00099## wherein at least one of R.sup.1 or R.sup.2 on C.sub..alpha. is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkylenecycloalkyl, and substituted alkylenecycloalkyl.
16. The conjugate of claim 15, wherein each of R.sup.1 and R.sup.2 on C.sub..alpha. is independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substitutedalkylenecycloalkyl, and all other non-C.sub..alpha. R.sup.1 and R.sup.2 variables are H.
17. The conjugate of claim 15, wherein R.sup.2on C.sub..alpha. is H.
18. The conjugate of claim 17, wherein R.sup.1 on C.sub..alpha. is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl.
19. The conjugate of claim 1, wherein X is a saturated cyclic or alicyclic hydrocarbon chain.
20. The conjugate of claim 19, wherein X has the structure: ##STR00100## and CYC.sub.a is a cycloalkylene group having "a" ring carbons, where the value of "a" ranges from 3 to 12; p and q are each independently 0 to 20, and p+q+a.ltoreq.20,R.sup.1, in each occurrence, is independently H or an organic radical that is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl, and R.sup.2, in eachoccurrence, is independently H or an organic radical that is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylenecycloalkyl, and substituted alkylenecycloalkyl.
21. The conjugate of claim 20, wherein p and q are each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8.
22. The conjugate of claim 20, wherein R.sup.1, in each occurrence, is independently H or an organic radical that is either lower alkyl or lower cycloalkyl, and R.sup.2, in each occurrence, is independently H or an organic radical that iseither lower alkyl or lower cycloalkyl.
23. The conjugate of claim 20, wherein a is selected from the group consisting of 5, 6, 7, 8 and 9.
24. The conjugate of claim 23, wherein a is 6 and CYC.sub.a is a 1,1-, 1,2-, 1,3- or 1,4-substituted cyclohexyl ring.
25. The conjugate of claim 24, wherein p and q each independently range from 0 to 4.
26. The conjugate of claim 24, wherein the substituents on said substituted cyclohexyl ring are cis.
27. The conjugate of claim 24, wherein the substituents on said substituted cyclohexyl ring are trans.
28. The conjugate of claim 20, wherein R.sup.1 and R.sup.2 are H in every occurrence.
29. The conjugate of claim 1, wherein POLY is selected from the group consisting of a poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, poly(acryloylmorpholine), and poly(oxyethylated polyol).
30. The conjugate of claim 29, wherein POLY is a poly(alkylene oxide).
31. The conjugate of claim 30, wherein POLY is a poly(ethylene glycol).
32. The conjugate of claim 31, wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety.
33. The conjugate of claim 32, wherein the end-capping moiety is independently selected from the group consisting of alkoxy, substituted alkoxy, alkenyloxy, substituted alkenyloxy, alkynyloxy, substituted alkynyloxy, aryloxy, and substitutedaryloxy.
34. The conjugate of claim 33, wherein the end-capping moiety is selected from the group consisting of methoxy, ethoxy, and benzyloxy.
35. The conjugate of claim 31, wherein the poly(ethylene glycol) has a nominal average molecular mass of from about 100 daltons to about 100,000 daltons.
36. The conjugate of claim 35, wherein the poly(ethylene glycol) has a nominal average molecular mass of from about 1,000 daltons to about 50,000 daltons.
37. The conjugate of claim 36, wherein the poly(ethylene glycol) has a nominal average molecular mass of from about 2,000 daltons to about 30,000 daltons.
38. The conjugate of claim 31, wherein said poly(ethylene glycol) has a structure selected from the group consisting of linear, branched and forked.
39. The conjugate of claim 1 having the structure: ##STR00101## wherein X and b are as previously defined, b' is 0 or 1, and X' is a hydrolytically stable linker comprising at least 3 contiguous saturated carbon atoms adjacent to the ringnitrogen atom.
40. The conjugate of claim 39, wherein said POLY is linear and the conjugate is homobifunctional. |
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